ADAM (a disintegrin and metalloproteinase) family is a membrane-associated protease having zinc in the catalytic site. ADAM17 cleaves a membrane-associated TNF-α (tumor necrosis factor alpha) and produces a soluble TNF-α, and is therefore referred to also as a TNF-α conversion enzyme (TACE). Soluble TNF-α causes inflammatory cytokine hypersecretion, cell apoptosis, obstruction of intracellular signal transduction, etc., and is to be a factor of bringing about cause and exacerbation of various diseases, as a result of primary and secondary tissue damages (see Non-Patent Reference 1). The pathological condition that TNF-α would participate in is considered to include typically rheumatoid arthritis (RA) as well as systemic lupus erythematosus (SLE), Crohn's disease, Behcet's disease, multiple sclerosis, Sjogren's syndrome, sepsis, acute infection, asthma, atopic dermatitis, psoriasis, etc.
ADAM17 (TACE) takes, as a substrate therefor, transforming growth factor (TGF)-α, heparin-binding EGF-like growth factor (HB-EGF), etc., in addition to the above-mentioned TNF-α. TGF-α is highly expressed in some human cancers, and is activated after released from cell membranes by the action of ADAM17 thereon. Regarding HB-EGF, when the transmembrane form thereof is cleaved by protease on the surface of a cell, this releases an EGF-like domain-containing extracellular domain and gives a soluble HB-EGF. It is known that the soluble HB-EGF is released from various tissues and cells such as epidermal cells, cardiocytes, vascular endothelial cells, smooth muscle cells, macrophages, etc., and causes cell growth and differentiation, inflammatory reaction, etc.
Consequently, a compound that inhibits ADAM17 is considered to be a promising therapeutic agent for various inflammatory disorders, various cancers, etc., and heretofore various studies have been made about ADAM17 inhibitors (see Non-Patent References 2 and 3, and Patent References 1 to 17).
As a substrate for ADAM10, another membrane-associated protease that belongs to the ADAM. family like ADAM17, there are Notch that participates in cancer progression, E-cadherin, epidermal growth factor (EGF), erythroblastic leukemia viral oncogene homolog 2 (ErbB2), etc., and it is reported that ADAM10 also releases TNF-α and HB-EGF, common to ADAM17. From these, it is suggested that ADAM10 would also acceleratingly participate in progression of pathological condition in disorders such as cancers, inflammations and others in which multiple factors would complexly interrelate with each other. Patent Reference 18 discloses an ADAM10 inhibitor; however, the compounds disclosed in Patent Reference 18 greatly differ from the compounds of the present invention in point of the structures thereof.